Complementary roles of gasotransmitters CO and H₂S in sleep apnea

Abstract

Sleep apnea, which is the periodic cessation of breathing during sleep, is a major health problem affecting over 10 million people in the United States and is associated with several sequelae, including hypertension and stroke. Clinical studies suggest that abnormal carotid body (CB) activity may be a driver of sleep apnea. Because gaseous molecules are important determinants of CB activity, aberrations in their signaling could lead to sleep apnea. Here, we report that mice deficient in heme oxygenase-2 (HO-2), which generates the gaseous molecule carbon monoxide (CO), exhibit sleep apnea characterized by high apnea and hypopnea indices during rapid eye movement (REM) sleep. Similar high apnea and hypopnea indices were also noted in prehypertensive spontaneously hypertensive (SH) rats, which are known to exhibit CB hyperactivity. We identified the gaseous molecule hydrogen sulfide (HS) as the major effector molecule driving apneas. Genetic ablation of the HS-synthesizing enzyme cystathionine-γ-lyase (CSE) normalized breathing in HO-2 mice. Pharmacologic inhibition of CSE with l-propargyl glycine prevented apneas in both HO-2 mice and SH rats. These observations demonstrate that dysregulated CO and HS signaling in the CB leads to apneas and suggest that CSE inhibition may be a useful therapeutic intervention for preventing CB-driven sleep apnea.

The role of hypoxia‐inducible factors in carotid body (patho) physiology

“…The increase in BP associated with chronic IH was not observed in Cse −/− mice or wild‐type mice treated with a CSE inhibitor, which lack H 2 S production in the CB (Peng et al . ). In contrast, Ho2 −/− mice have irregular breathing and frequent hypopnea and apnoea episodes, which include both central and obstructive events (Peng et al .…”

“…In contrast, Ho2 −/− mice have irregular breathing and frequent hypopnea and apnoea episodes, which include both central and obstructive events (Peng et al . ). Remarkably, all of these abnormalities were corrected by treatment with a CO donor or by treatment with a CSE inhibitor (Peng et al .…”

“…Remarkably, all of these abnormalities were corrected by treatment with a CO donor or by treatment with a CSE inhibitor (Peng et al . ). Hence, it is possible to integrate the regulatory circuits governed by gasotransmitters and O 2 ‐regulated transcription factors (Abstract figure).…”

Intelligent Metal Carbonyl Metal–Organic Framework Nanocomplex for Fluorescent Traceable H2O2‐Triggered CO Delivery

“…The emerging pharmacological activities of gaseous messenger molecules (such as NO, H 2 S, and CO) have recently attracted increasing interest to develop new therapeutic approaches for some major diseases including cancer and cardiovascular diseases . These endogenous gasotransmitters have specific molecular targets, powerful physiological regulation functions, and a high permeability across biomembranes, thereby exhibiting great advantages over traditional drugs.…”

An H2S‐Sensing/CO‐Releasing Flavonol That Operates via Logic Gates

“…[11–13] Perturbations in CO and H 2 S interplay are associated with sleep apnea and other (patho)physiological conditions. [12,14] Currently, there is limited knowledge of the interplay of CO and H 2 S and no molecular tools are available to study their interactions. This arena differs from that of NO/H 2 S interactions wherein a significant body of research is available.…”